Camptothecin is a cytotoxic quinoline alkaloid which inhibits the enzyme topoisomerase I. Camptothecin is naturally isolated from the bark and stem of Camptotheca acuminate (also referred to as “Happy Tree”) and used as a cancer treatment in traditional Chinese medicine. Camptothecin shows remarkable anticancer activity in preliminary clinical trials but also low solubility and considerable adverse side effects. Because of these disadvantages various semi-synthetic derivatives have been developed in order to increase the clinical benefits. Two of these semisynthetic derivatives have meanwhile been approved for use in chemotherapy, namely topotecan and irinotecan (reviewed, e.g., in Ulukan, H. and Swaan P. W. (2002). Drugs 62, 2039-2057).
7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin, that is, irinotecan, has a chemical structure according to Formula 1.

Currently available methods for the synthesis of irinotecan comprise the preparation of 7-ethyl-10-hydroxycamptothecin as intermediate product, to which 4-(1-piperidino)-1-piperidine is attached at the 10-position.
7-ethyl-10-hydroxycamptothecin is also commonly referred to as compound “SN 38” having a chemical structure according to Formula 2. SN38 is the therapeutically active “component” of irinotecan that exhibits cytostatic activity. On the other hand, however, SN38 is characterized by a low solubility in water and most other solvents that significantly interferes with the applicability of known synthesis schemes with respect to overall yield and purity of the final reaction product.

In order to prepare SN38, there are several ways of attaching the respective 7-ethyl and 10-hydroxyl groups to camptothecin which is used as a starting material.
A first synthesis route that is schematically illustrated in FIG. 1 comprises the introduction of a hydroxyl group at the 10-position of campothecin by means of a catalytic hydrogenation, followed by oxidation of the intermediate compound 1,2,6,7-tetrahydrocamptothecin by means of iodobenzene derivatives, thus resulting in the production of 10-hydroxycamptothecin. Subsequently, the 7-position of camptothecin is ethylated with propionic aldehyde in the presence of hydrogen peroxide or other peroxides and ferrous sulfate (i.e. iron(II) sulfate), that is, by means of classical Fenton's chemistry (Fenton, H. J. H. (1894) J. Chem. Soc. Trans. 65, 899-911).
A second synthesis route that is schematically illustrated in FIG. 2 comprises the ethylation of the 7-position of camptothecin with propionic aldehyde in the presence of hydrogen peroxide or other peroxides and ferrous sulfate (Fenton, H. J. H. (1894) supra), followed by introduction of a hydroxyl radical at the 10-position by a catalytic hydrogenation of 7-ethylcamptothecin, thus resulting in 7-ethyl-1,2,6,7-tetrahydrocamptothecin, and subsequent oxidation by means of, e.g., iodosobenzene, sodium periodate, or potassium peroxodisulfate. The overall yield of the desired reaction product SN38 is about 60% and purity is about 90%, respectively. This reaction pathway is further described inter alia in European patent 0 137 145 B1; U.S. Pat. No. 7,151,179 B2; U.S. Pat. No. 7,544,801 B2; and CN patent application 102718772 A.
Alternatively, the hydroxyl group at the 10-position of camptothecin can also be introduced photochemically. This scheme involves the oxidation of 7-ethyl-camptothecin which was prepared by employing the above-referenced Fenton's reaction in order to obtain 1-N-oxide-7-ethyl-camptothecin, followed by irradiation with ultraviolet light. This reaction pathway is further described inter alia in U.S. Pat. Nos. 4,473,692; and 4,545,880.
Yet another synthesis route is described in international patent publication WO 2005/019223. This pathway involves a condensation reaction of 7-ethyl-10-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in acetonitrile in the presence of 4-dimethylaminopyridine.
However, in all of the above methods, the yields are only at about 60-65% (as compared to the amount of starting material). Furthermore, the synthesis is significantly hampered by the low solubility of the reacting compounds. In order to overcome the latter problem, it was proposed to add acetic acid or trifluoroacetic acid as a co-solvent (Wu, D. (1998) Cascade Radical Cyclization: Application in the Development of New Anticancer Drug of Camptotecin Family and Development of new Synthetic Method. Master Thesis, University of Hawaii). This modification improved the reaction conditions but did not result in a significant increase of the overall yield.
For the subsequent synthesis of irinotecan, SN 38 is modified at the 10-position (i.e. the hydroxyl group) with a [4-(1-piperidino)-1-piperidino]carbonyl substituent according to Formula 3 by means of urea chloride or chloroformate in the presence of a strong organic base, such as triethylamine, 4-dimethylaminopyridine, or ethyldiisopropylamine).

Nevertheless, the overall yield of these reaction schemes is still comparably low. Furthermore, reaction intermediates are common side products, thus reducing the purity of the desired reaction product irinotecan.
Thus, there is a need for improved methods for the synthesis of irinotecan that overcome the above-referenced limitations. In particular, there is a requirement for a synthesis pathway that allows for an efficient production of irinotecan in high purity.
Accordingly, it is an object of the present invention to provide such a method.